Method of producing lysergic acid amide



ilnited rates Patnt O METHOD OF PRODUCING rvsnncrc ACID ANIIDE CameronAinsworth, Indianapolis, Ind., assignor to Eli Lilly and Company,Indianapolis, Ind., a corporation of Indiana No Drawing. Originalapplication August 27, 1954, Se-

rial No. 452,720. Divided and this application April 1, 1955, Serial No.498,781

2 Claims. (31. 260-2855) This invention relates to a novel method ofpreparing lysergic acid amide. More specifically, it relates to aprocess of converting lysergic acid hydrazide to lysergic acid amide.

Lysergic acid amide or ergine has long been known. Since the time of itsdiscovery, however, no satisfactory method of synthesizing thissubstance has been developed.

I have now discovered a process for converting lysergic acid hydrazide,a readily available starting material, directly to lysergic acid amide.My novel method comprises treating a solution of lysergic acid hydrazidewith Raney nickel at ordinary pressures. During the course of theconversion, ammonia is liberated. A preferred manner of carrying out myinvention is as follows: 1 g. of lysergic acid hydrazide is dissolved infrom 100 to 500 ml. of an inert solvent, preferably 95 percent ethanol,and about 15 g. of a heavy suspension of Raney nickel catalyst inethanol are added thereto. The mixture is then refluxed, with stirring,for about three hours. At this point the catalyst is filtered off, andthe filtrate is evaporated to dryness in vacuo. The resulting residuecomprising lysergic acid amide is then crystallized from a suitablesolvent.

Any solvent which is relatively inert to the action of Raney nickelcatalyst, can be used in my process, including alcohols, ethers,hydrocarbons, and the like. I usually employ 95 percent ethanol as asolvent, but other solvents such as methyl cyclohexane, dioxan, and thelike are equally operative. Additional suitable solvents will readily beapparent to anyone skilled in the art.

With respect to the hydrogen which cleaves the hydrazide grouping oflysergic acid hydrazide to an amide grouping and ammonia, it is thathydrogen which is present in the Raney nickel catalyst. The hydrogenarises during the process of preparing this catalyst and is adsorbed onthe catalyst in the amount of about 0.0025 mol. per gram of catalyst.Illustratively, 15 g. of a heavy suspension of catalyst in ethanolcontain about 14 2,755,235 Patented July 24, 1956 g. of dry Raney nickelcatalyst and about 0.035 mol. of hydrogen. The amount of Raney nickelcatalyst used in carrying out my process is that amount which willprovide at least one molecular equivalent of hydrogen for each molecularequivalent of lysergic acid hydrazide to e reacted. Preferably an excessof catalyst is employed. The amount of excess is not critical and can befrom 10 to 500 percent or more.

In carrying out my invention, I prefer to heat the mixture of lysergicacid hydrazide, solvent and Raney nickel catalyst with stirring to thereflux temperature of the solvent for at least tWo or three hours. Iflower temperatures are used, it is desirable to prolong the heatingperiod.

This invention is further illustrated by the following specific example:

Preparation of [ll-lysergic acid amide 1 g. of lysergic acid hydrazide(prepared by the method of Stoll et al., United States Patent No.2,090,429, issued August 17, 1937) was dissolved in 500 ml. of boilingethanol. 15 g. of a heavy suspension of Raney nickel catalyst were thenadded. The mixture was heated under reflux with stirring for two hours.The nickel catalyst was removed by filtration, and the filtrate wasevaporated to dryness. The residue Was treated with 10 ml. of methanol,and a solid mass resulted which was collected by filtration. The filtercake was dissolved in 5 ml. of warm dimethylformamide and 25 ml. ofmethanol were added. After standing at 5 C. for three days, 0.6 g. ofsolid crystals which formed, were collected. On heating on aFisher-Johns melting point block, a sample of these crystals, afterdrying, melted at -135 C. with gas evolution. They resolidified at aboutC. and then began to darken at about C., totally melting by about C. Thecompound was dried at 78 C. and 0.5 mm. pressure for four hours andanalysed for lysergic acid amide with one mol. of methanol ofcrystallization.

Analysis.Calcd for CreHrzNaO-CHaOH: C, 68.20; H, 7.07; N, 14.04. Found:C, 68.30; H, 7.27; N, 14.15.

This application is a division of my prior copending application SerialNo. 452,720, filed August 27, 1954, now abandoned.

I claim:

1. The process of preparing a lysergic acid amide from lysergic acidhydrazide which comprises heating lysergic acid hydrazide with an excessof Raney nickel catalyst in a solvent inert to hydrogenation with Raneynickel catalyst.

2. The process according to claim 1 wherein the inert solvent isethanol.

No references cited.

1. THE PROCESS OF PREPARING A LYSERGIC ACID AMIDE FROM LYSERGIC ACIDHYDRAZIDE WHICH COMPRISES HEATING LYSERGIC ACID HYDRAZIDE WITH AN EXCESSOF RANEY NICKEL CATALYST IN A SOLVENT INERT TO HYDROGENATION WITH RANEYNICKEL CATALYST.